Pharmacy 528 Echinocandins
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Rev. Med. Chir. Soc. Med. Nat., Iaşi – 2014 – vol. 118, no. 2 PHARMACY UPDATES ECHINOCANDINS - NEW ANTIFUNGAL AGENTS Cătălina Daniela Stan1, Cristina Tuchiluş2, C.I. Stan3 University of Medicine and Pharmacy “Grigore T. Popa” - Iaşi Faculty of Pharmacy 1. Drug Industry and Pharmaceutical Biotechnology Department Faculty of Medicine 2. Microbiology Department 3. Anatomy Department ECHINOCANDINS - NEW ANTIFUNGAL AGENTS (Abstract): Over the past 10-15 years, the number of clinically available antifungal agents has increased substantially, due to rise in the number of invasive fungal infections, which are a real problem for specialists. Echi- nocandins are the new class of antifungal agents available for clinical use. This class com- prises over 20 natural echinocandins and several semisynthetic ones. Natural echinocandins are not of clinical utility due to their toxicity and low water-solubility (which does not allow obtaining parenteral pharmaceutical forms), although they have good antifungal activity against Candida species. Consequently, semisynthetic echinocandins with minimal toxicity, good antifungal activity and high water-solubility were obtained. All echinocandins inhibit β-1,3-glucan-synthase, an essential component of the fungal cell wall. Echinocandins exhibit potent antifungal activity against key pathogenic fungi, including Candida species, Aspergil- lus species and Pneumocystis carinii. The available echinocandins lack in vitro activity against Cryptococcus neoformans. The semisynthetic echinocandins have great advantages, among which low toxicity, fast antifungal activity, favorable pharmacokinetics that allow once-daily administration. The echinocandins recently available for clinical use are: caspo- fungin, micafungin and anidulafungin. Keywords: MICAFUNGIN, ECHINOCANDINS, CASPOFUNGIN, PNEUMOCANDIN, ANIDULAFUNGIN Antifungal agents were discovered quite antifungal agents (tab. I) (1). late, although some species of pathogenic Nowadays, the natural antifungal agents fungi were discovered in 1835 (Beauvaria most often used in therapy are: polyenic bassiana). macrolides (nystatin, natamycin, amphoter- Despite intense research carried out in icin B), spiranic antibiotics (griseofulvin) order to discover new antifungal agents, and cyclic lipopeptide antibiotics (candins- they appeared later than the antibacterial the most popular being echinocandins). antibiotics on the pharmaceutical market. Other natural compounds are in differ- This happend because it was difficult to find ent stages of clinical testing: good antifungal agents with low toxicity. - papulacandins – glycolipid antibiotics Antifungal agents can be categorized produced by Papularia species; depending on how they are obtained as - pradimicins and benanomycins – an- synthetic antifungal agents and natural tracyclic antifungal agents isolated from 528 Echinocandins - new antifungal agents cultures of actinomycetes; gal agents isolated from cultures of acti- - nikkomycins and sardarins – antifun- nomycetes. TABLE I Natural antifungal agents No Antifungal agent Producing miroorganism Pharmaceutical products 1. Amphotericin B Streptomyces nodosus Fungizone, Fungilin 2. Azaserin Streptomyces spp. - 3. Candicidin Streptomyces griseus Levorin, Vanobid 4. Dermostatin Streptomyces viridogriseus Viridofulvin, Dermastatin Streptomyces cellulosae Streptomyces penticus 5. Fungicromin Streptomyces roseoluteus Cantricin Streptomyces griseus 6. Filipin Streptomyces filipenensis Filimarisin Penicillium griseofulvum Fulvicin, Grisactin, 7. Griseofulvin Penicillium janczewskii Fulcin, Grifulvin 8. Hachimycin Streptomyces hachijoensis Trichomicin, Trichonat 9. Hamycin Streptomyces pimprina Primamycin 10. Lucensomycin Streptomyces lucensis Etruscomicyn, Streptomyces natalensis Pimaricin, Natacyn Pimafu- 11. Natamycin Streptomyces chattanoogensis cin, Mycophyt Streptomyces noursei, Stamicin, Nistatin, 12. Nystatin Streptomyces aureus Fungicidin, Mycostatin 13. Partricin Streptomyces aureofaciens Ayfactin Paecilomyces varioti Bainier 14. Pecilocin Supral, Variotin var. antibioticus Streptomyces coelicolor var. 15. Perimicin Aminomycin aminophilus 16. Pirrolnitrin Pseudomonas pyrrocinia Pyroace Helminthosporium siccans 17. Siccanin Tackle Drechsler 18. Trichomycin Streptomyces hachijoensis Trichomycin Echinocandins were discovered in the patients (4, 5). Moreover, during the past 70’s and 80’s, being natural lipopeptidic decade, the incidence of invasive aspergillo- antibiotics active against the resistant strains sis has increased, especially in imunocom- of Candida and Aspergillus. These are the promised, cancer, and transplant patients (6). most recently aproved antifungal agents, Amphotericin B or fluconazole are the after years of intense research (2, 3). first-line therapeutic options in the treat- Candida species are the fourth leading ment of such fungal infections, but the cause of nosocomial infections in USA, utility of amphotericin B is limited due to mortality from candidiasis is reported to be its nephrotoxicity. Fluconazole is relatively 38% in imunocompromised persons, and safe, but there are already Candida species complications could appear in over 15% of resistant to it. 529 Cătălina Daniela Stan et al. Therefore, because invasive candidiasis cyclic hexapeptides molecules with the N- and aspergillosis are severe nosocomial linked acyl fatty acid ("side chain") with a infections, there was an urgent need for length of 14 to 18 carbon atoms (1). new antifungal agents. The recent discov- Echinocandins are a class represented ery and development of echinocandins is an by over 20 isolated natural products, which alternative to amphotericin B and flucona- are divided into several subclasses, and zole as first-line treatment for candidiasis. many semisynthetic analogues, derived Echinocandins are large amphiphilic from natural compounds (fig. 1). R3 R4 HO O R2 NH R NH 5 N O O R1 HN OH NH HO O R O N 6 HN R7 OH O OH HO No Echinocandin Fatty acid side chain (R5) 1. Echinocandin B Linoleic acid 2. Echinocandin C Linoleic acid 3. Echinocandin D Linoleic acid 4. Aculeacin Aγ Palmitic acid 5. Mulundocandin 12-Methylmyristoic acid 6. Sporiofungin A 10,12-Dimethylmyristoic acid 7. Pneumocandin A0 10,12-Dimethylmyristoic acid 8. Pneumocandin B0 10,12-Dimethylmyristoic acid Echinocandin R1 R2 R3 R4 R6 R7 Echinocandin B CH3 CH3 OH OH CH3 OH Echinocandin C CH3 CH3 OH OH CH3 H Echinocandin D CH3 CH3 H H CH3 H Aculeacin Aγ CH3 CH3 OH OH CH3 OH Mulundocandin H CH3 OH OH H OH Sporiofungin A CH2CONH2 CH3 OH OH H OH Pneumocandin A0 CH2CONH2 CH3 OH OH CH3 OH Pneumocandin B0 CH2CONH2 H OH OH CH3 OH Fig. 1. Natural echinocandins All natural echinocandins are active by the fungal cell wall biosynthesis, making it inhibiting enzyme 1,3-β-D-glucan synthe- easy to lysate (1, 7). The enzyme is not tase, being selective and noncompetitive present in the cell wall of higher animals, inhibitors of the essential components of which explains the very few side effects 530 Echinocandins - new antifungal agents caused by echinocandins. due to their toxicity (they are hemolytic They have the advantage of low toxici- substances), although they have very good ty, fast antifungal activity and favorable antifungal activity against Candida strains pharmacokinetic that allows once-daily (8). They also have low water solubility, administration (having large molecules which makes them difficult for parenteral should only be given intravenously). formulations. Thus, semisynthetic com- The spectrum of natural echinocandins pounds, non-toxic, with high antifungal is limited to Candida species (spp.), but activity and enhanced water solubility were some semisynthetic analogues have a wider obtained. Today three semisynthetic echi- spectrum that includes other endogenous nocandins, caspofungin, micafungin and fungi, such as: Aspergillus spp., Pneumo- anidulafungin are licensed for clinical use cystis carinii etc. None of these compounds (9). show activity againts Cryptococcus Starting with the natural candins isolat- neoformans strains. ed from the culture medium of Glarea Echinocandin B was first isolated and lozoyensis species a semisynthetic ana- identified as the major component of the logue of pneumocandin B0, called Caspo- class (which includes echinocandin C and fungin (fig. 2) was obtained and entered the D). It was isolated from the fermentation U.S. market in 2001 by Merck (CAN- broths of various fungi of the genus Asper- CIDAS - Merck, USA, vials 50 or 70 mg gillus nidulans and Aspergillus rugulosus lyophilized powder). In Europe it was in- in 1974, at the same time by the researchers troduced in therapy in 2002 (CANCIDAS, from Ciba-Geigy, Sandoz, and Eli-Lilly. Merck & Co. Inc., USA, MK-0991). The Researchers from Toyo Jozo have isolated pharmaceutical product contains caspofun- echinocandins from aculeacin class, and gin acetate a water-soluble salt of caspo- fermentations broths of Aspergillus acule- fungin. (C52H88N10O15·2C2H4O2). atus, those from Hoechst have isolated It has a good pharmacokinetics: 100% mulundocandin from Aspergillus sydowi bioavailability, high plasma protein binding and sporiofungin class was isolated from (97%) and a half-life of 9-11 h. It has a Criptosporiopsis spp. by Sandoz research- slow hepatic metabolism and a slow elimi- ers. The pneumocandin class, with the main nation from plasma with a clearence of 10- component pneumocandin B0, was isolated 12 mL/minute. Excretion of drug is through from the fermentations broths of some hepatic (34%) and renal (41%) routes.